This new application from the University of Pennsylvania School of Medicine (PENN) for a National Institute of Neurological Disorders and Stroke (NINDS) Morris K. Udall Parkinson's Disease Research Center of Excellence (Udall Center) builds on the continuing momentum of a team of PENN clinical and basic scientists to accomplish the overarching goals of this new multidisciplinary Parkinson's disease (PD) research program. Briefly, the goals of this Udall Center are to elucidate mechanisms of brain degeneration in patients with PD, especially those underlying poorly understood neuropsychiatric impairments. PD with dementia (PDD), which may be pathologically and clinically indistinguishable from dementia with Lewy bodies (DLB) frequently co-occurs with Alzheimer's disease (AD), and the Lewy body (LB) variant of AD is the most common subtype of AD. However, the reasons for the convergence of IBs and AD pathologies remain enigmatic. Here, we hypothesize that accumulations of oligomeric/fibrillar species of a-synuclein lead to neurodegeneration and neuropsychiatric deficits in addition to parkinsonism, which may be compounded by tau and Abeta pathologies seeded by alpha-synuclein oligomers/fibrils. To accomplish the goals of the PENN Udall Center, Projects 1 and 2 are patient-oriented studies designed to develop: 1) a disease-specific rating scale to assess the impact of cognitive impairment on daily function in PDD;and 2) a functional imaging study to better define the anatomic substrate of cognitive impairment in PD and PDD. Projects 3 and 4 bridge patient oriented studies and research on novel animal models of PD/PDD to clarify how the misfolding, fibrillization and aggregation of a-synuclein, tau and Abeta contribute to the neuron dysfunction and degeneration that result in cognitive impairments in PDD. These 4 highly integrated and synergistic Projects are supported by an Administrative Core (A), a Clinical and Education Core (B), a Neuropathology and Genetics (C) and a Data Management and Biostatistics Core (D). The PENN Udall Center investigators will accomplish the goals outlined above by working in a seamlessly interdisciplinary manner as well as by collaborating with other Udall Centers. Further, data, reagents, and resources generated by the PENN Udall Center will be shared with researchers at other Udall Centers. Thus, the PENN Udall Center team will contribute to improving the diagnosis and management of patients with PD, PDD, DLB and related disorders.